Branched Chain Amino Acids
Branched chain amino acids (leucine, isoleucine, and valine), or BCAA's, are a group of essential amino acids that play important roles in protein synthesis and energy production. In humans, about 15-25% of total protein intake is BCAA's, and dairy products are particularly high in them [1]. BCAA's make up 35-40% of the essential amino acids in body protein and 14% of the total amino acids in skeletal muscle [2]. One of the most important BCAA's is leucine, and estimates of dietary requirements for leucine range from 1-12 g daily [1]. The use of supplemental BCAA's has been researched for a variety of purposes, particularly in the treatment of liver failure and catabolic disease states [3], and also as a means to improve exercise performance.
There is a significant decrease in plasma leucine levels after aerobic, anaerobic, and strength exercise [4]. This is due to increased BCAA metabolism in muscle tissue [5]. Supplementation with leucine or BCAA's in both the short and long term prevents the exercise-induced decline in plasma BCAA's and increases muscle BCAA concentration [4-6]. The BCAA's are the only amino acids that are not readily degraded in the liver. Therefore, an increase in dietary BCAA's will reliably increase their concentration in blood and other tissues. Because BCAA's play important roles in promoting protein synthesis via multiple pathways, increasing their tissue content beyond the required amount may be beneficial, and increased availability of BCAA's will also increase production of other amino acids such as glutamine [1]. This article will review the research on and biochemical mechanisms of BCAA supplementation, particularly as they apply to the athlete.
Leucine & protein synthesis
In skeletal muscle, leucine stimulates protein synthesis through multiple independent mechanisms. The first mechanism is increased insulin secretion [7], and insulin is well known to increase body protein balance. However, leucine still stimulates protein synthesis in concentrations that do not increase insulin in vivo, and mechanisms by which leucine increases protein synthesis other than insulin secretion have been identified [7-9]. By itself, leucine stimulates protein synthesis through the mammalian target of rapamycin (mTOR) pathways, 70-kDa ribosomal protein S6 kinase activity, and enhances eIf4E-binding protein phosphorylation and the association of eukaryotic initiation factor (eIF)4E with eIF4G, effects that have been determined both in vitro and in vivo in humans [9-10]. These effects are directly mediated by leucine, rather than a metabolite, and the specifics of the process are not yet well established [7].
Multiple animal studies have confirmed the importance of leucine in protein synthesis and/or inhibition of protein catabolism. In vitro in rat muscles, leucine alone stimulates protein synthesis as effectively as all amino acids together [10]. Similarly, leucine and a complete meal were equally as effective at stimulating protein synthesis in fasted rats [11]. However, not all studies have yielded the same results, and this is likely due to the fact that other amino acids and factors are required to synthesize protein [9].
Studies have also been carried out in humans at rest, which primarily indicate that BCAA's inhibit protein breakdown under this condition. In studies with humans restricted to bed rest, BCAA supplementation decreases nitrogen losses when compared with non-essential amino acids [12]. While some studies indicate that BCAA administration decreases protein breakdown but doesn't increase protein synthesis in humans [9], others indicate that they do increase protein synthesis [8]. This is probably due to differences in study conditions. One study indicated that insulin infusion did not increase protein synthesis, but the combination of insulin and BCAA's did [13].
Further research has examined the interaction between exercise, BCAA's, and protein synthesis. Since BCAA concentrations are reduced during exercise, it is postulated that BCAA supplementation before, during, or after exercise may have a strong effect on improving muscle protein balance. A study in rats found that leucine stimulated muscle protein synthesis postexercise independently of increased plasma insulin [14]. In humans, studies have found increased protein synthesis and/or decreased protein breakdown when BCAA's are administered before, during, and after various types of exercise, although a few studies have not produced positive results [8, 11, 15-16].
Although it is clear that leucine is the most important of the BCAA's in stimulating protein synthesis, leucine supplementation alone is not recommended. This is because this can cause an amino acid imbalance, and although the other two BCAA's are less important, inhibiting them by increasing leucine intake may have negative consequences. Increasing dietary leucine decreases the concentrations of valine and isoleucine and blood and muscle tissue, and keeping a dietary balance of BCAA's is particularly important when compared with other amino acids [2]. A high amount of dietary leucine in the long-term depresses food intake and growth in various animals [10]. Thus, it is important to get all of the BCAA's together, rather than supplement with leucine alone.
BCAA's & exercise
BCAA's may also have other benefits for the athlete, especially when taken during or pre-workout. First, BCAA's may spare muscle and liver glycogen stores and increase fuel supply. Branched-chain oxo acid dehydrogenase (BCOADH) is the rate limiting step in the catabolism of BCAA's, and is normally inactive. However, exercise increases the activity of this enzyme [5], as does increasing the serum concentration of BCAA's [17]. This catabolism of BCAA results in the release of gluconeogenic precursors such as alanine and glutamine [1, 4, 8]. After being released from muscle, the alanine is used by the liver for gluconeogenesis [1]. In exercised rats, BCAA's increase serum glucose by 2-4 times compared to control [17] and BCAA supplementation increases alanine production during exercise in humans [18]. BCAA's also decreased plasma lactate with chronic supplementation (30 minutes before exercise) to triathletes, presumably by increasing the conversion rate of pyruvate to alanine [5]. In animals, BCAA and carbohydrates increase muscle glycogen concentration to a greater degree than carbohydrates alone [14]. Studies in humans have found that BCAA's have a glycogen sparing effect during exercise, although in some cases it is not statistically significant [8, 18]. However, other studies indicate that BCAA supplementation prior to exercise does not alter plasma glucose [1, 19].
An additional mechanism for improved exercise performance from BCAA's is inhibition of CNS fatigue. This was throroughly discussed in a review by Blomstrand [20]. Exercise causes an increase in serotonin levels, and this is one of the hypothesized mechanisms of CNS fatigue. This is supported by numerous facts, including the fact that some SSRI's have been shown to decrease exercise performance. BCAA's share the same transporter system with tryptophan (the serotonin precursor amino acid), so BCAA supplementation causes competitive inhibition of tryptophan transport to the brain, and this in turn reduces serotonin levels. Exercise increases the tryptophan/BCAA ratio in the bloodstream, and a BCAA supplement may prevent or reverse this. Further, animal studies find that tryptophan administration reduces exercise performance. This means that in theory, BCAA's could increase exercise performance by decreasing buildup of serotonin in the brain. Multiple studies indicate that BCAA supplements successfully change the BCAA/tryptophan plasma ratio, especially during more prolonged exercise [19-22].
Over the years, many studies have been done to determine if BCAA's improve exercise performance in humans, and they have produced varying results. In one crossover study, 13 subjects ingested BCAA or placebo prior to endurance exercise in the heat. The BCAA group cycled 153.1 minutes on average, whereas the placebo group averaged only 137.0 minutes [19]. Another study found that a BCAA supplement given prior to a 42 km marathon improved performance in slower runners, but not in faster ones [23]. In a study on seven male endurance-trained subjects who were glycogen depleted, BCAA's decreased ratings of perceived exertion by 7% and ratings of mental fatigue by 15% during 80 minutes of exercise, but performance was not increased [22]. In two other studies, one on endurance training and the other on high-intensity intermittent running, there was no performance difference between subjects who ingested BCAA's or BCAA's and carbohydrates [1, 21]. In a study on hypocaloric competitive wrestlers, a diet enriched with BCAA's did not improve strength or exercise ability, but the BCAA group lost more body fat [24]. However, two other studies, one in highly trained skiiers and another in patients with type II diabetes, indicate that BCAA's have no effect on body composition [25-26]. At this point, two independent reviews have concluded that the present evidence indicates that BCAA's do not improve endurance performance [27-28]. It would be more accurate to say that they can improve exercise performance under some conditions, but not others, and whether or not they have practical application is debatable.
A final possible benefit of BCAA supplementation is combatting immunosuppression caused by prolonged exercise. Supplementation of BCAA's to competing triathletes and runners increases plasma glutamine concentration, and one study indicates that increased glutamine can decrease the incidence of upper respiratory tract infections in endurance athletes [29]. On the other hand, other researchers contest the notion that increasing glutamine concentrations can combat exercise-induced immunosuppression [30].
Are BCAA supplements necessary?
Given the information above, there is significant evidence indicating various benefits of BCAA ingestion for athletes. However, the pertitent issue then becomes whether or not BCAA supplements have any advantage over ingestion of protein and/or carbohydrates, which are both significantly less expensive.
The first issue is whether or not BCAA's are superior to protein in stimulating protein synthesis. One study indicates that there is a decline in plasma leucine over five weeks of training in speed and strength athletes consuming 1.26 g protein per kg bodyweight daily, and that leucine supplementation prevents this decrease [4]. However, this study is only confirming a well known fact, which is that strength athletes need high amounts of dietary protein. Studies indicate that in bodybuilders and strength trainers, the amount of dietary protein needed to maximally stimulate protein synthesis is in the realm of 1.4-1.8 g/kg bodyweight (about .6-.7 g/lb), and also that most of these athletes consume well above this amount [31]. For example, a study in strength athletes compared daily dietary protein intakes of .86 g/kg, 1.40 g/kg, and 2.40 g/kg, and found that whole body protein synthesis was increased in the 1.40 g/kg group compared to the lower group, but not further increased in the 2.40 g/kg group. However, rates of leucine oxidation were much higher in the high protein group [32]. This means that if protein intake is adequate, it is doubtful that BCAA supplementation could further stimulate protein synthesis, as the extra amino acids will just be readily catabolized.
Perhaps even more enlightening is the work of Tipton et al., who conducted studies on the types and quantities of amino acids that increase protein synthesis in humans during and after exercise [33]. They compared 40 grams of mixed amino acids to 40 grams of essential amino acids (containing a much higher quantity of BCAA's) to compare their effectiveness in stimulating protein synthesis postexercise, and the two supplements provided a equivalent increases in protein synthesis. The authors then concluded that "there is a maximum rate of net synthesis attainable during hyperaminoacidemia after exercise," and that 40 grams of mixed amino acids is enough to maximally stimulate protein synthesis postexercise.
Another issue is that BCAA supplements are in the form of free-form amino acids, as opposed to a whole protein source. Supplement companies often claim that free-form amino acids are absorbed in greater quantity, more effectively, and more quickly, but this is contrary to the scientific evidence. In general, studies indicate that protein hydrolysates are utilized most effectively, followed by whole proteins, followed by free form amino acids. Intestinal transporters exist for both peptides and free amino acids, and peptides are absorbed more rapidly [34]. Peptides that are not absorbed via a transporter can be rapidly broken down enzymatically. Although not the best model for human athletes, studies in food-deprived rats being refed consistently find that whey protein hydrolysate leads to much higher degrees of weight gain and nitrogen retention than free form amino acids, with one study indicating that whole protein is in the middle in terms of effectiveness [35-36]. Comparative studies have also been done in humans. In healthy subjects, whole protein, protein hydrolysate, and free amino acids all resulted in similar nitrogen balance [37]. Another study in healthy humans found that a protein hydrolysate was absorbed equally as rapidly as free form aminos [38]. Ideally, a study more specific to the conditions in question would be available, but this research indicates that fast-digesting proteins could be just as or more effective than free form amino acids for use before or during exercise.
Carbohydrates may also provide many of the benefits of BCAA supplementation at a much lower cost. As mentioned above, two studies found that BCAA's and carbohydrates together did not provide a performance advantage over carbohydrates alone. Carbohydrates will obviously have glycogen sparing and glucose increasing properties as BCAA's do. Also, carbohydrate supplementation prevents the increase in tryptophan levels caused by exercise, although they may not be as effective as BCAA's [20]. Finally, carbohydrates also have glutamine-sparing and positive immune effects in athletes [39].
All in all, it would appear that the positive effects of BCAA's on protein synthesis can be achieved by a high protein diet and use of a fast-acting protein prior to and after exercise, and that most of the other possible benefits on exercise performance could be achieved equally as effectively by ingesting simple carbohydrates prior to exercise. If caloric intake must be limited at all costs, or if protein intake is inadequate, BCAA's may be useful in this respect. Also, a unique benefit of reduced CNS fatigue by decreasing tryptophan buildup cannot yet be discounted. Given the other properties of BCAA's described below, the usefulness of BCAA supplements can further be questioned.
Other effects of BCAA's
In addition to the effects on tryptophan levels, BCAA's may have other effects on the CNS, both direct and indirect. A well established property is that BCAA supplements reduce dopamine levels, an effect that occurs in many sample populations including healthy human volunteers (at doses of 10, 30, and 60 g) [40]. There are two possible reasons for this effect. The primary reason is that BCAA's competitively inhibit transport of phenylalanine and tyrosine to the brain (similar to the inhibition of tryptophan) [41]. Secondly, BCAA's also simultaneously lower the plasma levels of key amino acids required for neurotransmitter synthesis. This occurs because the BCAA's stimulate protein synthesis, but other amino acids are also required for protein synthesis. This issue does not occur with whole protein sources, which also provide the other amino acids required for protein synthesis. BCAA's also consequently lower levels of norepinephrine [42]. In conditions such as mania and hepatic encephalopathy, this effect of BCAA's can be beneficial [41-42]. However, decreased levels of NE and dopamine are generally not desirable in normal individuals. Functional changes induced in healthy humans by BCAA ingestion so far include impaired spatial memory and elevated plasma prolactin [40-41]. There is also a reference in the literature to BCAA ingestion increasing appetite [43].
BCAA's may also have effects on GABA transmission. When given to rats, BCAA's increase the pain threshold and increase the seizure threshold. This may be because they are used to produce glutamine in the brain, and glutamine is a precursor to GABA, but in all reality the exact mechanisms are far from being identified at this point, as there are many possibilities. [43]
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